Acute lymphoblastic leukemia as second primary tumor in a patient with retinoblastoma.

Second primary tumor (SPT) is defined as a second tumor that presents either simultaneously or after the diagnosis of an index tumor. Second primary malignancies are the leading cause of death in patients with heritable retinoblastoma (RB). Acute lymphoblastic leukemia (ALL), as SPT in RB patients, is extremely rare. To the best of our knowledge, only five cases of ALL as SPT in patients with RB has been documented in the literature. Herein, we report a case of a 6-year-old girl with bilateral RB, who developed ALL during the course of treatment of RB. This case highlights the importance of reviewing blood investigations regularly to diagnose leukemia as SPT in RB and also the necessity for proper counseling and lifelong follow-up in these patients.

Introduction

The improvement in diagnosis and treatment of retinoblastoma (RB) has increased the survival rates and most RB patients survive the disease and live into adulthood. Consequently, second primary nonocular tumors (SPT) are now the leading cause of death in patients with heritable RB. This high incidence of SPT inheritable RB is due to the presence of germline mutation of the RB1 gene in chromosome 13q14 in all the body cells. Thus, the initial step of oncogenesis is already present in all body cells from which the second cancer can eventually develop.

Leukemias as SPT in RB patients is less frequent.[1] To the best of our knowledge, there are only five cases of acute lymphoblastic leukemia (ALL) reported in the literature.[234] Herein, we report a rare, unusual case of a child with RB presenting with ALL as SPT within a very short span of initiation of treatment.

Case Report

A 6-year-old girl presented to us with painless diminution of vision in both eyes since 10 days. She was the first child born out of a nonconsanguineous marriage. There was a history of death due to malignancy in maternal aunt and grandmother, further details of which were not available. The best-corrected visual acuity was 20/126 in the right eye and counting finger close to face in left eye. Pupillary reflexes were sluggish in both eyes. On examination under anesthesia, the anterior segment of both eyes was unremarkable. Fundus examination revealed bilateral exophytic and endophytic white mass filling the vitreous cavity with diffuse vitreous and subretinal seeds and total retinal detachment [Figure 1a and b]. B-scan ultrasonography confirmed the presence of bilateral acoustically dense intraocular mass with calcification [Figure 1c and d]. Computed tomography scan of orbit also showed the same [Figure 1e and f]. Peripheral blood smear, bone marrow aspiration [Figure 1g and h], and cerebrospinal fluid cytology were within normal limits. Based on these clinical and radiological findings, a diagnosis of bilateral RB Group D (International Classification of RB) was made. The patient was started on high-dose chemotherapy (HDC) (vincristine, etoposide, and carboplatin) along with concurrent periocular carboplatin (POC) (20 mg/2 ml) injections. After completion of six cycles of HDC, there was a partial regression of main tumors with persistence of subretinal and vitreous seeds in both eyes [Figure 2a and b]. Owing to suboptimal response, another three cycles of HDC with concurrent bilateral POC injections were continued. Post nine cycles of HDC, persistent of subretinal and vitreous seeds were noted in both eyes [Figure 2c and d], and three more sessions of bilateral POC injection were planned. Examination under anesthesia after two sessions of POC revealed the recurrence of vitreous and subretinal seeds in both eyes [Figure 2e and f]. In view of worsening, the patient was advised to undergo bilateral orbital external beam radiotherapy (EBRT) 4600 cGy in 23 fractions (200 cGy/fraction). However, after receiving 15 fractions, the child had an episode of epistaxis. A complete blood count revealed a white blood cell count of 400,000 cells/mm3 and a platelet count of 55,000 cells/mm3. Peripheral blood smear showed lymphoblasts with Romanowsky stain which were not showing block positivity for periodic acid-Schiff stain and not staining with myeloperoxidase stain [Figure 3a and b]. Flowcytometry confirmed the diagnosis of pro-B-ALL [Figure 3c–j]. This confirmed the diagnosis of SPT of leukemia in this child. The child received systemic chemotherapy for leukemia. At 1-year follow-up, the child is doing well with complete remission of leukemia with no leukemic cells in peripheral blood smear or bone marrow. The RB in both eyes is regressed, and the child is on close follow-up.

Figure 1

Clinical picture at the time of presentation of the patient. Fundus photograph of right (a) and left (b) eyes showing intraocular mass with diffuse vitreous and subretinal seeds and total retinal detachment. B-scan ultrasonography of right (c) and left (d) eye showing bilateral acoustically dense intraocular mass with calcification with overlying retinal detachment. Computed tomography scan of orbit in axial (e) and coronal (f) cuts showing bilateral intraocular mass lesions with calcification. Peripheral blood smears (g) shows mature lymphocytes and adequate platelets (Giemsa, ×400). Bone marrow aspirate (h) shows all stages of hematopoietic cells with no evidence of abnormal cells (Giemsa, ×400)

Figure 2

Fundus findings during chemotherapy. Fundus photographs showing regressed solid tumor with persistence of subretinal (red arrow) and vitreous seeds (white arrow) in right (a) and left (b) eyes, post six cycles of systemic chemotherapy. Fundus photographs showing persistence of subretinal (red arrow) and vitreous seeds (white arrow) in right (c) and left (d) eyes post nine cycles of systemic chemotherapy. Fundus photographs showing recurrence of vitreous (white arrow) and subretinal seeds (red arrow) in the periphery of the right (e) and left (f) eyes, post two sessions of additional periocular carboplatin injections

Figure 3

Peripheral blood smears and flow cytometry at the time of detection of acute lymphoblastic leukemia. (a) Peripheral blood smears in acute lymphoblastic leukemia showing lymphoblasts (Romanowsky, ×400). (b) Peripheral blood smears in acute lymphoblastic leukemia showing myeloperoxidase stain negative lymphoblasts and few myeloperoxidase positive neutrophils (myeloperoxidase, ×400). Flow cytometry confirming the diagnosis of Pro B acute lymphoblastic leukemia with flow cytoblasts showing positivity for (c) CD 45 (d) CD 34 (e) HLA-DR (f) Tdt (g) CD 19 (h) CD 38 (i) CD 79a and (j) CD 15 markers

Discussion

SPT is defined as a second tumor that presents either simultaneously or after the diagnosis of an index tumor. Mutational inactivation of both alleles of the RB1 tumor suppressor gene in the developing retina initiates RB. About 40% of RB patients have a hereditary predisposition caused by heterozygous germline mutation in the RB1 gene.[5] These children who survive heritable RB are at a high risk for developing and dying from subsequent SPTs. EBRT administered before the age of 12 months is known to increase this risk.[6] Our patient had bilateral RB and thus suggestive of heritable RB and at risk for SPTs. The first publication in this regard was by Reese et al. in 1949 where he had attributed the second malignancy to radiation alone.[7] Subsequent studies demonstrated that second tumors developed in 14% of bilateral RB patients who underwent enucleation without irradiation. Although the occurrence of these tumors is well recognized, there is controversy regarding their incidence because all the studies differ substantially. Cohort studies have shown the cumulative incidence of second cancer at 50 years after diagnosis of heritable RB to be 36-51% compared with 5-5.7% after nonheritable RB.[8]

Chemotherapy-induced leukemia in RB patients is well documented in literature. Gombos et al. found 15 cases of secondary acute myeloid leukemia (AML) in patients who received chemotherapy for RB.[9] Turaka et al. reported only one case of AML in 245 patients with RB-treated with chemotherapy.[10] It is interesting to note that there are no documented cases of ALL secondary to chemotherapy in literature. The diagnosis of chemotherapy-induced leukemia was less likely in our case since the interval between completion of chemotherapy and onset of disease was <2.5 months.

Leukemia, as SPT, is very rare with a reported incidence of 2.4%.[1] To the best of our knowledge, only five cases of ALL as SPT to RB has been reported.[234] Hoefnagel et al. reported a case of ALL 8 years after only surgical treatment of a patient with unilateral RB.[2] Abramson reported a case of ALL in a patient with unilateral disease among 711 patients with RB.[3] Woo and Harbour did a literature review of 676 published cases of SPTs in patients with RB and found only five cases of ALL.[4] The reason behind chemotherapy inducing only AML and not ALL is unclear. Interplay of factors such as tumor biology, type of RB1 gene defect, chemotherapy, radiotherapy, and age at presentation could have influenced the development of ALL in our patient. Thus, lifelong follow-up of all heritable RB survivors with regular review of blood investigations with knowledge of the condition helps in establishing the diagnosis.

Financial support and sponsorship

Support provided by Operation Eyesight Institute for Eye Cancer (SK) and Hyderabad Eye Research Foundation (SK), Hyderabad, India.

Conflicts of interest

There are no conflicts of interest.